Colorectal cancer is the second leading cause of cancer-related deaths in the United States and one of the most commonly diagnosed cancers. The majority of cases are classified as sporadic in nature. However, hereditary influence is commonly found. Azoxymethane (AOM), an alkylating carcinogen, predominantly causes tumors in the distal colon of rodents. Genetic characterization of the AOM pathway through the use of mouse strains that differ in sensitivity to AOM carcinogenesis will provide a better understanding of the molecular mechanism of the AOM-induced toxic response. Furthermore, the genetic variation represented by the inbred mice used in this study will provide a model for the genetic variation exhibited by human populations. Thus, we will be able to identify potential susceptibility genes that predispose humans to colorectal cancer. The specific aims of this proposal will address these objectives by: (1) determining whether strain specific susceptibility to AOM induced colorectal cancer translates to differences in tumor morphology and pathway disruption; (2) correlating acute changes in AOM induced gene expression profiles with colorectal cancer susceptibility; and (3) identifying DNA adducts formed from acute exposure to AOM.